Activation of lysosomal iron triggers ferroptosis in cancer.
| Autor: | Rodriguez R; Institut Curie, CNRS., Cañeque T; Institut Curie., Baron L; Institut Curie., Müller S; Institut Curie, CNRS, INSERM, PSL Research University, Equipe Labellisée Ligue Contre le Cancer., Carmona A; Harvard T. H. Chan School of Public Health., Colombeau L; Institut Curie., Versini A; Institut Curie., Sabatier M; Harvard T. H. Chan School of Public Health., Sampaio J; Institut Curie., Mishima E; Institute of Metabolism and Cell Death, Molecular Targets & Therapeutics Center, Helmholtz Munich, Neuherberg, Germany., Picard-Bernes A; Institut Curie., Solier S; Institut Curie., Zheng J; Helmholtz Zentrum München., Proneth B; Helmholtz Munich., Thoidingjam L; Institut Curie., Gaillet C; Institut Curie., Grimaud L; ENS., Fraser C; Harvard University., Szylo K; Harvard T. H. Chan School of Public Health., Bonnet C; Inserm., Charafe E; Inserm., Ginestier C; Inserm., Santofimia P; Inserm., Dusetti N; Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France., Iovanna J; Centre de Recherche en cancerelogie de Marseille., Sa Cunha A; APHP., Pittau G; APHP., Hammel P; APHP., Tzanis D; Institut Curie., Bonvalot S; Institut Curie., Watson S; Insitut Curie., Stockwell B; Columbia University Irving Medical Center., Conrad M; Institute of Metabolism and Cell Death, Molecular Targets & Therapeutics Center, Helmholtz Munich, Neuherberg, Germany., Ubellacker J; Harvard T.H. Chan School of Public Health. |
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| Jazyk: | angličtina |
| Zdroj: | Research square [Res Sq] 2024 Apr 08. Date of Electronic Publication: 2024 Apr 08. |
| DOI: | 10.21203/rs.3.rs-4165774/v1 |
| Abstrakt: | Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death referred to as ferroptosis 1-3 . Identifying where this chemistry takes place in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Whereas genetic approaches have revealed underlying mechanisms of lipid peroxide detoxification 1,4,5 , small molecules can provide unparalleled spatiotemporal control of the chemistry at work 6 . Here, we show that the ferroptosis inhibitor liproxstatin-1 (Lip-1) exerts a protective activity by inactivating iron in lysosomes. Based on this, we designed the bifunctional compound fentomycin that targets phospholipids at the plasma membrane and activates iron in lysosomes upon endocytosis, promoting oxidative degradation of phospholipids and ferroptosis. Fentomycin effectively kills primary sarcoma and pancreatic ductal adenocarcinoma cells. It acts as a lipolysis-targeting chimera (LIPTAC), preferentially targeting iron-rich CD44 high cell-subpopulations 7,8 associated with the metastatic disease and drug resistance 9,10 . Furthermore, we demonstrate that fentomycin also depletes CD44 high cells in vivo and reduces intranodal tumour growth in an immunocompetent murine model of breast cancer metastasis. These data demonstrate that lysosomal iron triggers ferroptosis and that lysosomal iron redox chemistry can be exploited for therapeutic benefits. Competing Interests: Additional Declarations: Yes there is potential Competing Interest. Institut Curie filed a patent application EP 24315029 related to LIPolysis-TArgeting Chimera to Induce Ferroptosis in Cancer. M.C. and B.P. hold patents for some of the compounds described herein, and are co-founders and shareholders of ROSCUE Therapeutics. B.R.S. is an inventor on patents and patent applications involving ferroptosis; co-founded and serves as a consultant to ProJenX, Inc. and Exarta Therapeutics; holds equity in Sonata Therapeutics; serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP. |
| Databáze: | MEDLINE |
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